Multiple Sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS (central nervous system) that damages the fatty myelin sheaths around the axons of the brain and spinal cord. This damage, destruction, and loss or scarring of the myelin sheaths (sclerosis or plaques) results in a broad spectrum of symptoms. MS is a chronic, disabling disease that affects about 400,000 people in the United States and nearly 2.5 million people worldwide. MS substantially and adversely affects the quality of life of each individual, with symptoms that include loss of muscle control and strength, fatigue, weakness, loss of vision, spasticity, balance, sensation, bladder and bowel problems, numbness, vision loss, tremors, and adverse mental function such as depression. In the United States alone MS care is estimated to cost nearly $13 billion per year.
Inflammatory cytokines and its receptors have an important role in the progression of MS lesions, and pro- and anti-inflammatory cytokine levels have been found to correlate with changes in MS disease activity. Currently, available treatments usually focus on strategies to treat relapses (oral prednisone and i.v. methylprednisolone), manage symptoms and reduce the progress of the disease with Disease Modifying Drugs (DMDs). It includes relapsing-remitting MS (RRMS) drugs such as Immunomodulatory (β-interferons) therapeutics (Avonex, Betaseron, Rebif and Extavia), Monoclonal Antibodies (Tysabri, Lemtrada), other immunosuppressants (Mitoxantrone), Copaxone (glatiramer acetate injection) and oral agents; Teriflunomide, Fingolimod but none of these medications is a cure or prevent recurring symptoms. In addition to existing oral DMDs such as Fingolimod, and recently approved Tecfidera (BG-12 or Dimethyl Fumarate) and other experimental agents yet to be approved are in Phase III of clinical development such as Laquinimod, and Masitinib (oral immunomodulators) have been reported to cause opportunistic infections, antibody stimulation, liver and kidney toxicities. Target specific inhibitors or antagonists should promote myelination, neuronal repair, neuroprotection. Inhibiting the disease and halting neurodegeneration should eliminate many of these adverse events.
Presently, oral DMT drugs such as Fingolimod, Cladribine, and Tecfidera—as well as about 46 other experimental agents in various stages of clinical development such as Laquinimode, and Masitinib—have been reported to cause serious adverse events including opportunistic infections, antibody stimulation, and liver and kidney toxicities. Thus, there is a continuing need for effective MS drugs with better toxicity profiles. Target specific inhibitors or antagonists should promote myelination, neuronal repair, halting neurodegeneration, and should eliminate many of these adverse events.
The evidence supporting the risk-benefit profiles for available agents including emerging mAb (Alemtuzumab, Ocrelizumab and Daclizumab) DMTs is yet to fully emerge. Many of these approved and experimental agents yet to be approved create serious adverse events including opportunistic infections, antibody stimulation, and liver and kidney toxicities. Therefore, MS is still a significant target for innovative therapies that can have immunotherapeutic and/or neuroprotective effects on the disease. This opportunity has strengthened our research focus on clinically relevant RORγt, as an attractive target for the treatment of MS. RORγt as a nuclear hormone receptor that is a key regulator of T helper type 17 (Th17) cell differentiation. Th17 cells are normally produced in response to infection, but have been linked to the development of autoimmune diseases. A few pre-clinical stage lead RORγt and RORγ inverse agonists have been reported. For example, azole-type fungicides, T0901317, SR1001, ursolic acid, VPR-66, digoxin, and hexafluoro-substituted sulphamoyl thiazoles had efficacy in autoimmune encephalomyelitis (EAE) mice models. At least dozen companies; Lycera/Merck, Karo Bio/Pfizer, Phenex/J&J, Orphagen/JT (OR-1050/T0901317, 5 μM), Tempero/GSK (TMP-778, GSK-805), Exelixis/BMS, Teijin/Amgen, Cognoci (COG112), Innovimmune (INV-17), Visionary, 4SC Discovery and Genentech, have small molecule RORγt programs in preclinical stage of development. Identification of brain penetrant, RORγt specific antagonists that rescue myelin destruction, restore the axons of the brain and spinal cord following oral administration will be a significant approach for developing MS therapeutics. The substituted 2, 3-dihydro-1H-inden-1-one class of compounds claimed in Formula I discovered as potent, brain penetrant, orally available RORγt antagonist, and a small molecule candidate compounds as new drug entities for the treatment of such diseases claimed.
The present invention includes small molecule antagonists targeting Retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ. RORγt is the key transcription factor and is the master regulator of human Th17 (T helper 17) cells, a unique subset of CD4+ T cells. RORγt controls cellular differentiation, function and Interleukin IL-17 (IL-17 producing T-helper lymphocytes) release by Th17 cells and helps mediate the immunopathology of human autoimmune diseases such as Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, COPD, Pain, Obesity, Diabetes, Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseases and Cancer.
In addition, the substituted 2,3-dihydro-1H-inden-1-one Retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ antagonists of the present invention may be useful in the treatment of multiple cancers, includes gastric, colon cancers, chronic myelogenic leukemia (CML), acute myelogenic leukemia (AML), squamous cell, and bladder carcinomas, medulloblastoma, hepatocellular carcinoma, multiple myeloma, bladder, glioblastoma multiform (GBM), breast and ovarian cancers, Ewing's sarcoma and bone associated cancer diseases. The methods of treatment of the claims of Formula I and its associated claims in the application comprise of administering a safe and effective dose of a compounds according to Formula I or a pharmaceutically-acceptable salt, formulations thereof to a human patients.
Induction of autoimmune MS conditions in mice using Myelin Oligodendrocyte Glycoprotein (MOG) or Proteolipid Protein (PLP) immunization causes RORγt activation and differentiation of Th17 cells that recruit proinflammatory cytokines IL-17A (IL-17), IL-17F, IL-21 and IL-22 leads to sclerotic myelin and damaged oligodendrocytes. Mice with RORγt deficient T cells have attenuated disease and lack tissue-infiltrating Th17 cells. Hence, RORγt is a key regulator of immune homeostasis and is a potential therapeutic target for Multiple Sclerosis. Using proprietary internal company proprietary Fragment-Field Drug Design (FFDD) based technology and uniquely designed specific RORγt isoform assays a novel, potent small molecule substituted 2, 3-dihydro-1H-inden-1-one series and are specific RORγt antagonist (inverse agonist) and demonstrated its RORγt activity in an RORγt-activated IL-17A Prom/LUCPorter assay in HEK 293 cells, in IL-17 release from CD4+ T cells assays, as well as inhibition of IL-17 production in vivo in BALB/c mouse experiments and the effect of substituted 2, 3-dihydro-1H-inden-1-one series of Formula I compounds on MOG35-55 induced in C57/BL6 or BALB/c mice, PLP139-151 (Proteolipid Protein) induced in SJL/J mice and Theiler's Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) in female BALB/c mice induced Acute/Relapsing EAE model in female SJL/J mice is claimed in this application.